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Nat Commun. 2016 Jan 5;7:10258. doi: 10.1038/ncomms10258.

The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival.

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Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
West Roxbury Division, VA Boston Healthcare System, West Roxbury, MA 02132, USA.
Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
Cancer Science Institute of Singapore, Department of Medicine, National University of Singapore, Singapore 117599, Singapore.
Division of Metabolic Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.


KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma (MM) has not been elucidated. Here we identify KDM3A-KLF2-IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A-KLF2-IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.

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